Glucagon-like peptide-1 and peptide YY multi-agonism with GEP44 to optimize weight loss and glycemic control while reducing gastrointestinal side effects: the future of anti-obesity pharmacotherapy?

Obesity is a chronic, multifactorial disease that has reached epidemic status. The glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) is a key therapeutic target to achieve weight loss and glycemic control in obesity and type 2 diabetes mellitus. Tirzepatide and retatrutide, the latest generation of GLP-1-incorporating multi-agonists, target multiple receptors in complementary systems to achieve marked and sustained weight loss. However, the associated gastrointestinal (GI) side effects ( e.g. , nausea, vomiting, diarrhea, abdominal pain) that often hinder patient compliance underscore a remaining need for therapies with better tolerability. GEP44, a novel, monomeric, chimeric peptide structurally based on native GLP-1, the GLP-1RA exendin-4 (Ex-4), and the gut-derived hormone peptide YY3-36 (PYY 3-36 ), is an agonist at the GLP-1R and multiple neuropeptide Y (NPY) receptors. This review summarizes the design rationale for GEP44 and preclinical evidence supporting its beneficial metabolic effects and tolerability. Like GLP-1, PYY 3–36 is associated with decreased food intake (FI), and co-administration of GLP-1RA and PYY 3–36 elicits synergistic food intake (FI)- and body weight (BW)-reducing effects with similar or enhanced blood glucose (BG)-lowering effects. Studies examining the efficacy of GEP44 to promote weight loss and improve glucoregulation in lean vs. diet-induced obese rodents report that peripheral administration generally decreases BW, FI, and insulin resistance and increases EE at equivalent or greater magnitudes than those observed with single GLP-1RAs in a GLP-1R-dependent manner with improved GI tolerability. These beneficial actions reflect GEP44’s potential to expand the mechanistic scope of anti-obesity medications.